Mucus hypersecretion and goblet cell metaplasia are central features of many lung diseases. No treatments exist for goblet cell metaplasia in Th2-low asthma, chronic bronchitis, and cystic fibrosis. In contrast, Th2-high asthma has well-described drivers (e.g., IL13) and available treatments. Patients with untreated goblet cell metaplasia suffer disabling symptoms, frequent hospitalizations, and high healthcare costs. The overall objective of this proposal is to determine the role of heat-shock protein 90 (HSP90) in airway goblet cell metaplasia. My central hypothesis is that inhibition of HSP90 induces goblet to ciliated cell transdifferentiation. Robust preliminary data supports this hypothesis: 1) IL13 induces goblet cell metaplasia in human airway epithelia, with a negative correlation between goblet and ciliated cell abundance, 2) HSP90 inhibition reverts IL13- and IL17-induced goblet cell metaplasia without inducing cell death, and 3) HSP90 inhibition blocks ERBB2/EGFR signaling in IL13-stimulated airway epithelia. I propose three specific aims: Specific Aim 1: Is HSP90 required for goblet cell metaplasia in airway epithelia? I will address this aim using human and mouse deletion of HSP90 gene isoforms. I will expose gene-edited mice and human airway cells in vitro to IL13 or IL17. Specific Aim 2: Does HSP90 inhibition induce transdifferentiation of goblet cells into ciliated cells? I will address this aim with lineage tracing of human airway cells exposed to IL13, IL17, and HSP90 inhibitors. Specific Aim 3: Is apical membrane HSP90 localization required for ERBB2 signaling in goblet cell metaplasia? I will address this aim with protein phosphorylation and localization assays. I will expose human airway epithelia to HSP90 blocking antibodies before and after IL13 or IL17 stimulation. With the completion of this proposal, I expect to have identified novel mechanisms and treatment targets to revert airway goblet cell metaplasia. Treating goblet cell metaplasia caused by various triggers (e.g., IL13 and IL17) may improve many lung diseases. The University of Iowa has a longstanding history of support to its junior faculty. My mentor, Dr. Zabner, is also a Latino Physician-Scientist. Dr. Zabner is a national leader in epithelial lung biology, cystic fibrosis, and gene therapy. He has mentored several K awardees to independence and successful careers as Physician-Scientists. This K-award will expand my research skills to developmental biology and viral vectors. These tools may enable gene therapy in the future and support a cure for chronic bronchitis.